Serine-linked PARP1 auto-modification controls PARP inhibitor response

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Serine-linked PARP1 auto-modification controls PARP inhibitor response. / Prokhorova, Evgeniia; Zobel, Florian; Smith, Rebecca; Zentout, Siham; Gibbs-Seymour, Ian; Schützenhofer, Kira; Peters, Alessandra; Groslambert, Joséphine; Zorzini, Valentina; Agnew, Thomas; Brognard, John; Nielsen, Michael L; Ahel, Dragana; Huet, Sébastien; Suskiewicz, Marcin J; Ahel, Ivan.

In: Nature Communications, Vol. 12, No. 1, 4055, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Prokhorova, E, Zobel, F, Smith, R, Zentout, S, Gibbs-Seymour, I, Schützenhofer, K, Peters, A, Groslambert, J, Zorzini, V, Agnew, T, Brognard, J, Nielsen, ML, Ahel, D, Huet, S, Suskiewicz, MJ & Ahel, I 2021, 'Serine-linked PARP1 auto-modification controls PARP inhibitor response', Nature Communications, vol. 12, no. 1, 4055. https://doi.org/10.1038/s41467-021-24361-9

APA

Prokhorova, E., Zobel, F., Smith, R., Zentout, S., Gibbs-Seymour, I., Schützenhofer, K., Peters, A., Groslambert, J., Zorzini, V., Agnew, T., Brognard, J., Nielsen, M. L., Ahel, D., Huet, S., Suskiewicz, M. J., & Ahel, I. (2021). Serine-linked PARP1 auto-modification controls PARP inhibitor response. Nature Communications, 12(1), [4055]. https://doi.org/10.1038/s41467-021-24361-9

Vancouver

Prokhorova E, Zobel F, Smith R, Zentout S, Gibbs-Seymour I, Schützenhofer K et al. Serine-linked PARP1 auto-modification controls PARP inhibitor response. Nature Communications. 2021;12(1). 4055. https://doi.org/10.1038/s41467-021-24361-9

Author

Prokhorova, Evgeniia ; Zobel, Florian ; Smith, Rebecca ; Zentout, Siham ; Gibbs-Seymour, Ian ; Schützenhofer, Kira ; Peters, Alessandra ; Groslambert, Joséphine ; Zorzini, Valentina ; Agnew, Thomas ; Brognard, John ; Nielsen, Michael L ; Ahel, Dragana ; Huet, Sébastien ; Suskiewicz, Marcin J ; Ahel, Ivan. / Serine-linked PARP1 auto-modification controls PARP inhibitor response. In: Nature Communications. 2021 ; Vol. 12, No. 1.

Bibtex

@article{1cca2e71bdd24a9aa9d77a2ccaaf2c5a,
title = "Serine-linked PARP1 auto-modification controls PARP inhibitor response",
abstract = "Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.",
author = "Evgeniia Prokhorova and Florian Zobel and Rebecca Smith and Siham Zentout and Ian Gibbs-Seymour and Kira Sch{\"u}tzenhofer and Alessandra Peters and Jos{\'e}phine Groslambert and Valentina Zorzini and Thomas Agnew and John Brognard and Nielsen, {Michael L} and Dragana Ahel and S{\'e}bastien Huet and Suskiewicz, {Marcin J} and Ivan Ahel",
year = "2021",
doi = "10.1038/s41467-021-24361-9",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Serine-linked PARP1 auto-modification controls PARP inhibitor response

AU - Prokhorova, Evgeniia

AU - Zobel, Florian

AU - Smith, Rebecca

AU - Zentout, Siham

AU - Gibbs-Seymour, Ian

AU - Schützenhofer, Kira

AU - Peters, Alessandra

AU - Groslambert, Joséphine

AU - Zorzini, Valentina

AU - Agnew, Thomas

AU - Brognard, John

AU - Nielsen, Michael L

AU - Ahel, Dragana

AU - Huet, Sébastien

AU - Suskiewicz, Marcin J

AU - Ahel, Ivan

PY - 2021

Y1 - 2021

N2 - Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.

AB - Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.

U2 - 10.1038/s41467-021-24361-9

DO - 10.1038/s41467-021-24361-9

M3 - Journal article

C2 - 34210965

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4055

ER -

ID: 273584531